대한한의학회지제 34 권제 3 호 (2013 년 9 월 ) J Korean Med. 2013;34(3):86-95 pissn 1010-0695 eissn 2288-3339 Original Article 연교패독산 ( 윤다래, 홍성인, 노현인, 이서라, 이인희, 류재환 경희대학교한의과대학내과학교실, 경희대학교한방병원동서협진실 Observation of Inflammatory Marker Levels in Sprague-Dawley Rats with Youngyopaedoc-san-related Anti-atherogenic Effect Da-rae Yoon, Sung-in Hong, Hyun-in Noh, Seo-ra Yi, In-hee Lee, Jae-hwan Lew Dept. of Oriental Internal Medicine, College of Oriental Medicine, Kyunhee University Dept. of East-west integrated medicine, Kyung-Hee Oriental Medical Hospital Objectives: Sprague-Dawley rats were fed with high fat diet, and atherogenic changes were seen in the aorta. However, when Sprague-Dawley rats were fed with a high fat diet and administered Youngyopaedoc-san together, these atherogenic changes were rarely seen. This study was aimed to find the inflammatory marker level changes in Sprague-Dawley rats with Youngyopaedoc-san-related anti-atherogenic effect. Methods: The extract from Youngyopaedoc-san was made by the pharmacy department of Kyung-hee Oriental Medical Hospital. The animals were divided into five groups: normal diet, high fat diet, high fat diet with Youngyopaedoc-san, high fat diet with Vytorin, and high fat diet with Youngyopaedoc-san and Vytorin. A light microscopic image of a cross section taken from the aorta of the Sprague-Dawley rat was analyzed. We compared inflammatory marker levels among the five groups. Results: The complex of Youngyopaedoc-san and Vytorin has more anti-atherogenic effects in the aorta of Sprague-Dawley rats fed with high fat diet than Vytorin alone. Youngyopaedoc-san has inhibitory effect on the increase of IFN-γ and IL-2 levels. The difference on eosinophil levels of each group was statistically significant, but the eosinophil level of each group was within normal limits, so the difference on eosinophil levels was not clinically significant. Conclusions: Youngyopaedoc-san-related anti-atherogenic effect could be a result of inhibitory mechanism on IFN-γ and IL-2. Key Words : Youngyopaedoc-san, high fat diet, atherosclerosis, histology, inflammatory marker 서론동맥경화는다양한요인에의해혈관의구조에장애가일어나동맥벽안에지질이나세포외기질의비정상적인축적이일어나는경화성변화를말한다. 동 맥경화의발생은내막의손상으로시작이되는데고지혈증과같은화학적장애는내막손상의원인이된다. 내막의손상을계기로동맥벽안으로침투된지질단백 (low density lipoprotein, LDL) 은이물질로간주되어내피세포에서 cytokine이형성되는등염증 Received:30 May 2013 Revised:17 July 2013 Accepted:17 July 2013 Correspondence to: 류재환 (Jae-hwan Lew) 서울시동대문구회기동 1 번지경희의료원한방병원 3313 호동서협진실의국 Tel : +82-2-958-1812, E-mail : intmed@khu.ac.kr 86
윤다래외 5 명 : 연교패독산 ( (345) Constitute Herbs Weight Ostericii Radix 3.0g Angelicae Pubescentis Radix 3.0g Bupleuri Radix 3.0g Peucedani Radix 3.0g Platycodi Radix 3.0g Cnidii Rhizoma 3.0g Poria 3.0g Lonicerae Flos 3.0g Aurantii Fructus 3.0g Forsythiae Fructus 3.0g Saposhnikovia Radix 3.0g Schizonepetae Spica 3.0g Menthae Herba 3.0g Glycyrrhizae Radix 3.0g Total amount 42g 반응이시작되고결국에는동맥경화성플라크를형성하여동맥경화로인한합병증을일으킨다 1). 때문에염증반응에주목하여관상동맥의동맥경화로나타나는심혈관질환의병태생리에대해이해하고심혈관질환의예방및치료에접근할수있다 2). 연교패독산은고금의감에처음기록되었으며동의보감에서옹저초기치료에응용한다고기록 3) 하고있으며감기 4), 알레르기 5), 박탈성피부염 6), 단독 7), 봉와직염 8) 에대한항염증효과및기관지상피세포에서 Thymus and activation-regulated chemokine (TARC) 억제 9), carageenan으로유도된염증반응억제 10) 등에대한기존의보고가있다. 동맥경화는내막손상이원인이되어염증반응이시작되며, 연교패독산은항염증효과가보고되었기때문에, 연교패독산으로항동맥경화효과를살펴보고자 Sprague Dawley rat을대상으로본연구를실시하였다. 재료및방법 1. 재료 1) 약재실험에서사용한연교패독산은동의보감에수록된처방을기준으로하였으며 1첩당각구성약재는다음과같으며 (Table 1) 하루복용량을 2첩으로계산하 였다. 각구성약재는경희대학교경희의료원한방병원에서구입하였다. 2) 검액의제조연교패독산 1800g을둥근플라스크에넣고증류수 2000ml를가하여가열-추출을 2회하고추출액을여과지로여과하였다. 이들을 rotary evaporator (vaccum evaporator, EYELA, Japan) 로감압농축한다음 deep freezer (ultra low temperature freezer, 일신바이오, 한국 ) 로 70.6 에서동결건조하여연교패독산건조분말을 400g( 수득률 22.22%) 을얻었다. 제조된연교패독산에대해서는 high performance liquid chromatography (HPLC) 분석으로확인하였다. 3) 양성대조약물 Merck Sharp & Dohme (MSD) 에서나온 Vytorin 10/40 (ezetimibe 10mg, simvastatin 40mg) 을복용법에따라계산하여 8.3mg/kg/day로 oral gavage로투여하였다. 4) 실험동물실험동물의식이및사육, 실험에이용된동물은중앙실험동물 ( 주 ) 에서구입한체중 200g 전후의 6주령수컷 Sprague Dawley Rat으로 8마리씩 5군으로나누어 2주간적응시킨후 3주간사육하였다. 실험동물은사육실에서사육하였으며사육실온도는 87
(346) 대한한의학회지제 34 권제 3 호 (2013 년 9 월 ) Ingredient Proportion (%) Moisture 11.03 Protein 20.89 Fat 4.75 Fiber 5.77 Ash 6.04 Calcium 1.24 Phosphorus 0.55 etc. 49.73 Total amount 100 Ingredient Proportion (%) by weight Protein 23.5 Cardohydrate 27.3 Fat 34.3 etc. 14.9 Total amount 100 Ingredient Proportion (%) kcal from Protein 18.4 Cardohydrate 21.3 Fat 60.3 Total amount 100 Casein 26.50 L-Cystine 0.40 Maltodextrin 16.00 Sucrose 9.00 Lard 31.00 Soybean Oil 3.00 Cellulose 6.55 Mineral Mix AIN-93G-MX (94046) 4.80 Calcium Phosphate, dibasic 0.34 Vitamin Mix V10001, AIN-93-VX (94047) 2.10 Choline Bitartrate 0.30 Blue Food Color 0.01 Total amount 100 24±0.5, 습도 45±5% 이며, 매일광주기및암주기를각각 12시간이되도록조절하였다. 실험동물은각군의 8마리씩을 stainless steel cage에분류하여사육하였고식이와물은자유공급하였다. 5) 식이 처음 2주간의적응기간에는모든실험군의 Sprague Dawley rats에 normal diet ( 일반쥐사료, Research Diets) 를섭취시켰으며, 그다음 3주간의실험기간에는 normal diet와 high fat diet (Harlan, TD.06414 Adjusted Calories Diet (60/Fat)) 를군별로섭취시켰다. 88
윤다래외 5 명 : 연교패독산 ( (347) High fat diet 실험식이의구성은다음과같다 (Table 2.3). 중량을기준으로본다면 Normal diet에서는 fat의함량이 4.75%, high fat diet에서는 34.3% 이다. 반면열량을기준으로살펴본다면 high fat diet 에서 fat이차지하는부분은 60.3% 가되어중량을기준으로한것보다월등히높다. Flow Cytometry 로측정하였고 WBC는 Cell pack, Cell sheath, Stromatolyer-FB, Sulforlyser (SYSMEX, Japan) 을사용하였다. S-Neutrophil, Lymphocyte, Monocyte, Eosinophil은 CBC시약 +Stromatolyser- 4DL, Stromatolyer-IM, Stromatolyer-4DS (SYSMEX, Japan) 을사용하였다. 2. 방법 1) 실험군배정실험은 6주령수컷 Sprague Dawley rat 8마리씩을정상군 (Normal group), 대조군 (Control group), 연교패독산투여군, 연교패독산과 Vytorin 병용투여군, Vytorin 투여군으로나누어진행하였다. 정상군을제외한나머지군은 3주간 60kcal% fat의고지방식이를투여하였다. 연교패독산투여군은매일 1회동일한시간에연교패독산분말 3g/Kg/day를 10cc/kg 증류수에희석하여경구투여하였고, Vytorin 투여군은 Vytorin 8.3mg/kg/day를 10cc/kg 증류수에희석하여경구투여하였고, 연교패독산과 Vytorin 병용투여군에서는연교패독산분말 3g/Kg/day와 Vytorin 8.3mg/kg/day를 10cc/kg 증류수에희석하여경구투여하였다. 약물을투여하지않는정상군과대조군에서는증류수를같은량으로 10cc/kg 투여하였다. 2) 대동맥조직의처리및관찰적출된대동맥조직의표본제작을위해 10% formalin 용액에서 12~24시간고정시킨후충분히수세하였다. 탈수는 60~100% alcohol 을순차적으로 1 시간씩침투시킨후 xylene을투명제로하여파라핀블록을제작하였다. 제작된블록은 microtome을이용하여 3~4 의두께로절편을만들어탈파라핀및함수과정을거친다음 hematoxyline과 eosin 일반염색을실시하여광학현미경과컴퓨터영상분석기로대동맥을기준으로축적된지방의면적비율을관찰및사진촬영 (200배율, 400배율 ) 하였다. 3) Inflammatory marker level 측정 (1) White blood cell (WBC), Segmentaion neutrophil (S-Neutrophil), Lymphocyte, Monocyte, Eosinophil 측정 (2) C-reactive protein (CRP) 측정 Immunoturbidimetric assay로측정하였고 CRP (Latex) HS (Roche, Germany) 를사용하였다. (3) Cytokine 측정배양후상층액을수집하여 Enzyme-linked immunosorbent assay (ELISA) 방법으로 IFN-γ, IL-1 β, IL-2, IL-4, IL-12p70, TNF-α, IL-6을측정하였다. 수집한시표와 commercial kit에주어진표준 cytokine을 cytokine-specific monoclonal antibody 로도포된 ELISA plate (Bio-Plex Pro Assays, Bio-Rad Laboratories, USA) 에넣고 plate를 37 에서 2시간동안배양한뒤세척하였다. 효소가결합된 cytokinespecific polyclonal antibody 를다시 plate에넣고 3 7 에서 2시간동안배양하고세척하였다. 기질용액을넣고상온에서 30분동안방치하여반응하도록한뒤 2 N sulfuric acid로반응을정지시켰다. ELISA plate의각 well의흡광도는 450nm에서 ELISA reader (Bio-Plex Manager 6.0 Software, USA) 로측정하였다. (4) 통계처리결과는평균 ± 표준편차로표시하였다. 각군간통계학적인차이를보기위해 SPSS (version:20.0k; SPSS InC. Chicago, Illinois, USA) 를이용하여정규성검정을한결과정규성을만족하지않았으므로비모수검정인 Kruskal Wallis test를실시하여유의성여부를검증하였고 Kruskal Wallis test에서유의성이인정된경우 Mann-Whitney test를실시하여대조군과비교하였으며, p값이 0.05미만인경우유의성을인정하였다. 89
(348) 대한한의학회지제 34 권제 3 호 (2013 년 9 월 ) As shown in (A) and (B), the innermost layer, the endothelial cells are supported by a thin bed of subendothelial connective tissue that rest on thick sheet of elastic fiber. In (C) and (D), The arrow shows subendothelial foam cell deposits. In (E), The arrow shows the tunica intima composed of endothelial cells and elastic lamina tightly. The foamy vacuolization and fat deposits in the tunica media mean degenerative changes of wall. In (F), The arrow shows degenerative chages in the tunica media at the bifurcation of aorta. In (G), The arrow shows the foamy vacuolization in the tunica intima apparently. In (H), The arrow shows the vacuolization and the fat infiltration in the tunica media. In (I), The arrow shows minor fat deposits in the subendothelial layer. In (J), The arrow slightly shows minor vacuolizaion in the endothelial layer. It is almost normal. Animals were divided into five groups: Normal, fed with normal diet; Control, fed with high fat diet; YG, fed with high fat diet with Youngyopaedoc-san; VY, fed with high fat diet with Vytorin; and YG+VY, fed with high fat diet with Youngyopaedoc-san and Vytorin. 90
윤다래외 5 명 : 연교패독산 ( (349) 결과 게나타나는것을확인할수있었다. 1. 대동맥조직의관찰정상군은내피세포배열이일정하며탄력섬유에잘부착되어있었다. 고지방식이를투여한대조군에서는내피세포아래층에거품양상으로세포가변형된소견이나타난다. 고지방식이와함께연교패독산을투여한군에서는대체적으로정상소견이나부분적으로거품양상으로세포가변성된소견및지방침착이있었다. 고지방식이와 Vytorin을투여한군에서는거품양상으로세포가변성된소견이잘나타난다. 고지방식이와연교패독산 Vytorin을함께투여한군에서는전반적으로미미한지방침착이보이지만정상소견이다 (Fig1). 광학현미경관찰에서정상군과달리고지방식이투여군에서지방변성이관찰되었으며고지방식이와함께연교패독산, Vytorin 각각을단독투여한군에서도부분적인변화가관찰된다. 반면에고지방식이와함께연교패독산과 Vytorin을병용투여한군에서는지방침착이미미하여연교패독산또는 Vytorin 단독투여군보다연교패독산및 Vytorin 복합투여군에서조직학적소견이양호하 2. Inflammatory marker level 측정 13가지항목중 WBC, S-Neutrophil, Lymphocyte, Monocyte, hs-crp, IL-1β, IL-4, IL-12p70, TNF-α, IL-6에대해서는정상군, 고지방식이를투여한대조군, 고지방식이와함께연교패독산, Vytorin을단독혹은병용투여한다섯군에대하여통계학적으로유의성있는차이는검증되지않았다. Eosinophil, IFN-γ, IL-2에대해서는군에따라통계학적으로의미가있는차이가검증되었다. Eosinophil은고지방식이를투여한대조군에비해 Vytorin을투여한고지방식이군에서통계학적으로유의미하게상승하였다. 연교패독산과 Vytorin을병용투여한고지방식이군에서는통계학적으로유의미하게감소하였으며측정값은모든실험군에서정상범위에속하였다. IFN-γ에대해서는고지방식이와함께연교패독산을투여한군에서 IFN-γ가대조군에비해통계학적으로유의성있게낮게측정되었다. 고지방식이와함께 Vytorin을단독투여한군에서는오히려 IFN-γ가높게측정되었으나통계학적인유의성은 Normal Control YG VY YG+VY WBC (10³/ μl ) 8.73±2.16 8.07±2.55 7.11±3.05 7.02±2.41 7.35±2.92 S-Neutrophil (%) 12.89±4.99 13.65±2.79 15.25±4.56 15.14±2.11 13.43±3.71 Lymphocyte (%) 83.70±5.88 82.49±2.77 80.59±4.92 79.39±3.18 83.40±4.08 Monocyte (%) 1.45±0.67 1.50±0.46 1.49±0.50 1.45±0.52 1.54±0.40 Eosinophil (%) 1.75±0.90 2.14±0.50 2.50±1.67 3.83±2.51* 1.45±0.42* (P=0.008) (P=0.035) hs-crp (mg/l) 1.40±0.20 1.43±0.74 1.43±0.07 1.41±0.83 1.49±1.25 IFN-γ (ρg/ μl ) 74.15±45.76 137.96±67.52 46.34±15.37* 151.03±117.38 61.56±35.15* IL-1β (ρg/ μl ) 300.56±118.97 339.00±102.63 485.28±248.43 341.33±110.23 294.84±71.95 IL-2 (ρg/ μl ) 315.58±98.38 749.08±417.33 305.60±134.92* 655.06±268.36 495.38±237.24 IL-4 (ρg/ μl ) 40.44±32.87 55.69±38.73 26.00±15.49 38.24±16.34 13.42±7.08 IL-12p70 (ρg/ μl ) 1.68±0.11 2.24±0.48 2.00±0.00 2.13±0.51 4.08±3.27 TNF-α (ρg/ μl ) 464.82±154.05 940.92±427.56 1533.76±991.65 1240.23±587.81 1553.17±989.89 IL-6 (ρg/ μl ) 385.04±147.93 498.14±252.64 958.64±903.15 452.69±67.08 460.67±208.90 The results are expressed as mean±s.d (n=8). The significant differences with the control group were statistically calculated by Mann-Whitney test. YG: The group administered Youngyopaedoc-san, VY: The group administered Vytorin, YG+VY: The group administered Youngyopaedoc-san and Vytorin. 91
(350) 대한한의학회지제 34 권제 3 호 (2013 년 9 월 ) 없었다. 반면에고지방식이와함께연교패독산과 Vytorin을병용투여한군에서는 IFN-γ가대조군에비해통계학적으로유의성있게감소하였다. IL-2에대해서는고지방식이와함께연교패독산을투여한군에서대조군에비해 IL-2가통계학적으로유의성있게감소하였다. 고지방식이와함께 Vytorin을단독투여한군에서도 IL-2의감소되는경향이있었으나통계학적인유의성은없었다. 연교패독산과 Vytorin을병용투여한군에서는 Vytorin 단독투여군보다 IL-2가더많이감소하는경향성을확인할수있었으나통계학적인유의성은없었다 (Table4). 고찰동맥경화는동맥벽안에지질등의축적이일어나는경화성변화를말하는데내막의손상으로시작된다. 손상된내막을통해침투된지질단백 (low density lipoprotein, LDL) 으로인해 cytokine 이형성되는등염증반응이일어나게되므로 1) 관상동맥의동맥경화에의한심혈관질환의예방및치료에접근하기위해서는그기전이되는염증반응을주의깊게살펴볼필요가있다 2). 연교패독산은기존의문헌에서항염증효과가보고된대표적인처방이다. 연교패독산은명나라때서적인고금의감에처음기록되었는데이후동의보감에서는,,, 이라고하여옹저초기에오한발열이심하고심하면머리가아프고손발이당겨상한과비슷한것을치료 3) 한다고기록하고있다. 연교패독산의처방구성을살펴보면,,,,,,,,,,,,, 로구성되어있는데이중에서,,,, 는에속하며은,, 은이고은이며은,, 는, 은, 는에속하며 11) 이중에,,,,,,, 는항염증약물로분류할수있다 12). 연교패독산에대한양성대조약물로서지방흡수 억제제및 HMG-CoA reductase inhibitors 복합제인 MSD의 Vytorin 10/40 (ezetimibe 10mg, simvastatin 40mg) 을선정하였다. HMG-CoA reductase는 cholesterol 대사를조절하는주요효소로서, HMG-CoA reductase 활성억제는고콜레스테롤혈증과동맥경화를예방치료하는데유용한것 13) 으로알려져있다. 한약양약병용투여에대해서는혈부축어탕과 Aspirin 14), 소풍활혈탕과 Clopidogrel 15) 등기존의연구에서한약, 양약단독투여군및한약양약병용투여군의효과를비교한자료등에근거하여본연구에서는 Sprague Dawley rat을대상으로 3주간고지방식이와함께연교패독산을투여함과동시에연교패독산과항동맥경화제인 Vytorin 병용투여및 Vytorin 단독투여하여고지방식이섭취로인한대동맥의동맥경화성변화가조직학적으로확인되었으나연교패독산동시복용으로항동맥경화효과가나타난 Sprague Dawley rat을대상으로염증지표의변화를관찰하고자하였다. 고지방식이를투여한대조군에서는내피세포아래층에거품양상으로세포가변형된소견이나타났으며고지방식이와함께연교패독산또는 Vytorin은단독으로투여한군에서는거품양상으로세포가변성된소견이나타난것에비해연교패독산 Vytorin을함께투여한군에서는지방침착의정도가미약하여전반적으로정상소견임을확인할수있었다 (Fig1). 염증지표를측정한결과 WBC, S-Neutrophil, Lymphocyte, Monocyte, hs-crp에대하여각군간에통계학적인유의성있는차이는검증되지않았다. 특이한것은고지방식이와함께 Vytorin을투여한실험군에서 Eosinophil이상승하였으나고지방식이와함께연교패독산과 Vytorin을병용투여한실험군에서는오히려감소한것이다. Vytorin 단독투여군과연교패독산 Vytorin 복합투여군에서의 Eosinophil의차이는대조군과비교했을때통계학적으로유의성이입증되었다. 통계학적으로유의성있는차이가관찰되기는하나정상군을포함한모든실험군에서 Eosinophil 혈중농도가정상범위로측정되고있기때문에임상적으 92
윤다래외 5 명 : 연교패독산 ( (351) 로시사하는바는크지않다고생각된다. IFN-γ, IL-1β, IL-2, IL-4, IL-12p70, TNF-α, IL-6의측정값을분석한결과고지방식이를투여한대조군에서 IFN-γ, IL-2, TNF-α가통계학적으로유의성있게상승하여고지방식이로인해 IFN-γ, IL-2, TNF-α이상승한것으로해석된다. 고지방식이와함께연교패독산을단독투여한경우및연교패독산을 Vytorin과함께병용투여한모든경우에대해 IFN-γ의통계학적으로유의성있는감소가확인되어연교패독산이 IFN-γ 감소시키는기전에작용하는것으로추측된다. 고지방식이와함께연교패독산을단독투여한군에서고지방식이만을투여한대조군보다 IL-2이통계학적으로유의성있게감소하여연교패독산이단독적으로 IL-2의상승억제에영향을주는것으로사료된다. 염증지표와관련하여 WBC, S-Neutrophil, Lymphocyte, Monocyte, hs-crp 및 Eosinophil의혈청학적검사소견에서뚜렷한통계학적, 임상적의미를찾기어려우나 IFN-γ, IL-2 등일부의 cytokine에대해서위와같은차이가나타나는것에대해서는동맥경화성변화에관여하는염증반응이전신적으로나타나는염증반응이아니기때문에혈청학적소견에서뚜렷한염증소견이나타나지않은것으로생각된다. T 세포에의해분비되는 cytokine은 type 과 type 로나누는데 type 은염증반응을증가시키는 cytokine을분비하여 T세포와단핵구를활성화시키고증식시키는반응이다. IFN-γ, IL-2은위와같은 type 에속하는 cytokine 16) 이라 IFN-γ, IL-2 증식이억제되었다는것은항염증작용으로해석할수있다. 이상의결과를볼때, 연교패독산단독투여및 Vytorin과의병용투여군에서조직학적으로확인된대동맥의항동맥경화효과는 IFN-γ, IL-2의상승을막아주는연교패독산의항염증작용과관련성이있을것으로생각된다. Clendenen의연구 17) 에서도본연구와마찬가지로연령, BMI, 흡연과같은만성질환의위험인자들과염증관련지표와상관성이있는것으로추정되고있다. 본연구의제한점은다음과같다. 고지방식이를통해동물모델을만든다른연구를살펴보면 사용한 Sprague Dawley rat이 3주령 ~6주령, 체중 50~180 g을대상으로 4주 ~8주간의고지방식이를투여하였다 18-22). 이에비해본연구에서는 6주령, 200 g 전후의 Sprague Dawley rat을대상으로 2주간의적응기간을가진후 3주간의고지방식이를투여하였기때문에고지방식이가상대적으로영향을적게미쳤다고생각한다. 본연구에서는대동맥조직의동맥경화성변화를광학현미경관찰을통해정성적으로파악하였는데향후의추가적인실험연구에서동맥경화성변화의정도를보다세밀하고구체적으로정량적으로파악한다면각군간에보이는조직학적소견의차이에대하여통계학적으로엄격히검증할수있을뿐만아니라염증지표와의상관성에대해서도보다구체적인해석이가능할것으로기대된다. 결론 3주간고지방식섭취로인해동맥경화가유발되었으나연교패독산복용으로항동맥경화효과가나타난 Sprague Dawley rat을대상으로염증지표의변화를관찰하여얻은결론은다음과같다. 1. 연교패독산또는 Vytorin을단독으로투여하는것보다연교패독산과 Vytorin을함께투여하는것이고지방식이로인해유발되는거품세포변성및지방침착등대동맥조직의동맥경화성변화를억제하는데효과적이다. 2. 고지방식이와함께연교패독산을단독투여한경우및연교패독산을 Vytorin과함께병용투여한경우 IFN-γ가통계학적으로유의성있게낮았고, 고지방식이만을투여한대조군보다고지방식이와함께연교패독산을단독투여한군에서 IL-2이통계학적으로유의성있게감소하였다. 3. Eosinophil에서통계학적으로유의성있는차이가검증되었으나모든군이정상참고치에속해임상적의미는없다. 93
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